1. The Center for Professional Advancement
Lyophilization Technology The theory and practice of freeze-drying of pharmaceuticals
M. Kamat and M. Yelvigi
The Center for Professional Advancement
January 30-31, 2013
New Jersey, USA
M. Kamat Jan, 2013

2. History Freeze-dried plasma/serum in WWII
Even today: At-least 10 donors, 2 years RT, 200 mL water for constitution
Bacteria/vaccines
Food industry: coffee, fruits
Military Rations/Astronaut Food/Hikers' food
Museum articles
Restoration of old artifacts (sunken ships, water-damaged libraries)
M. Kamat Jan, 2013

3. M. Kamat Jan, 2013

4. Lyophilized Pharmaceuticals
More than 140 lyophilized injectables
Ampoules, syringes, vials, and large bottles
> 30 biologicals, vaccines
Freeze-dried skin grafts and tissues
Quick-dissolve oral tablets (Claritin Reditabs)
M. Kamat Jan, 2013

5. Definition
Lyophilization is a coupled heat-mass-transfer process where the frozen solvent, usually water, is removed initially by sublimation under the conditions of reduced pressure and sub-zero temperatures, and then by desorption under the conditions of reduced pressure and above zero temperatures to yield a dry product.
Whereas, freeze-drying may be defined as vacuum drying below 0 ºC (coffee, cereals, space food, animals etc.)
Keywords:
Required Undesirable
Frozen Instability
Sublimation Collapse/meltback
Desorption Vial breakage
Dry Product High moisture
Reconstitution Problems
We will use freeze drying and lyophilization as synonymous for this course
M. Kamat Jan, 2013

6. Why Lyophilization of Pharmaceuticals
Advantages:
1. Stability: Aqueous Stability
To make sure that no more than 10% degradation in 2-4 years
Thermal Stability : High temperature conventional drying may not be suitable
2. Improved Product Characteristics:
Improved kinetic solubility (because of porosity and very large surface area)
Usually freeze-dried product is amorphous
Variable recon. volume to get conc. (SubC conc.?)
3. Other Advantages:
Shipping advantage (low weight)
Less interaction with primary package of highly alkaline solutions
Less problems with glass delamination
M. Kamat Jan, 2013

7. Why Lyophilization of Pharmaceuticals
Advantages: cont.
4. Accuracy of dosage
Ease of filling complex formulation as a solution
Doses as low as 0.1 mL (vaccines, GF etc.)
5. Well controlled headspace
Nitrogen, Argon (oxygen and some time Freon too)
Vacuum
Ease of Operation:
Liquid filling operation: Automatic, accurate, well controlled (well established)
In-line sterilization filtration in the final container
M. Kamat Jan, 2013

8. Stability of Solution and Lyophilized Forms
* From Package Insert Information
M. Kamat Jan, 2013

9. If thermal stability is not an issue why not powder fill?
API/Excipients substance need to be Sterile
Handling: aseptic powder, bins, etc.
Fill Accuracy
<100mg powder filling (auger, piston) is difficult
Particulate issues
Dusting problem
Environmental Factors:
Humidity, Oxygen, Electrostatic Charge
Powder Characteristics (difficult):
Flowability and segregation
Particle Size, PSD, blend uniformity, Bulk density, cohesiveness)
Most of the large dose antibiotics (penicillins, cephalosporins) are powder filled in billions of quantities
M. Kamat Jan, 2013

10. Disadvantage of lyophilization
Additional unit process
One more thing that can go wrong and that too irreversibly !!)
Costly and complex equipment needing greater maintenance
Transfer and scale-up issues compared to solution products
Long cycles (up to even 7 days): Cleaning, sterilization, leak-testing may add another 24 hours
M. Kamat Jan, 2013

11. Physical Chemistry of Lyophilization:
Points to Consider :
Behavior of water during freezing
Heat Transfer Phenomenon
Mass Transfer Phenomenon
Coupling of Heat and Mass Transfer
Requirements of Process
M. Kamat Jan, 2013

12. Physical Chemistry of Lyophilization:
Points to Consider
Behavior of solutions during freezing
Sublimation Process
Heat Transfer Phenomenon
Mass Transfer Phenomenon
Coupling of Heat and Mass Transfer
Requirements of Process
M. Kamat Jan, 2013

13. Phase diagram of water Triple point
Sublimation occurs between the solid and the vapor phase regions.
Since only two phases are present (solid line), solid ice and the vapor ice are in equilibrium.
The diagram also says that once Temp of ice is fixed, the vapor pressure over ice is automatically fixed, and vice-a-versa.
M. Kamat Jan, 2013

14. Ref. point 1 mBar = 1000 µbar = 750 mTorr or 750 microns
0.33 mBar = 200 microns
1 atmosphere = 760 mm = 760,000 mTorr
M. Kamat Jan, 2013

15. M. Kamat Jan, 2013

16. Energetic of Phase Change
In Regular Evaporation Drying :
Vaporization
Liquid Water Water Vapor (Hvap)
In Sublimation Drying (Lyophilization)
Sublimation (no liquid)
Ice Water Vapor (Hsub)
M. Kamat Jan, 2013

17. Energetic of Phase Change
Sublimation Drying (Lyophilization)
Sublimation (no liquid)
Ice Vapor state (Hsub)
Sublimation involves solid, liquid, and gas transitions and need energy
H2Oice (-40 C) H2Ovapor (25 C), Hsub
1. H2Oice (-40 C) H2Oice (0 C), H1
2. H2Oice (0 C) H2Oliq (0 C), H2
3. H2Oliq (0 C) H2Oliq (25 C), H3
4. H2Oliq (25 C) H2Ovapor (25 C), H4
Adding all these reactions, Hsub = H1 + H2 + H3 + H4
M. Kamat Jan, 2013

18. Heat Energy Must Be Provided for Sublimation to Continue:
How much heat to be supplied ?
676 calories/gm of ice to be sublimed at ºC
Latent heat of fusion (78 Calories) + Latent heat of vaporization (598 Calories)
If excess heat (more than required for phase change) is supplied, the heat will be used to raise the temperature of the product (not just for phase change) and .....Eventually melt the ice.
M. Kamat Jan, 2013

19. Probe in pot-full of water
Boiling Water in Kettle
Temp=100 C
Temp= ~600 C
Boiling Water
(Phase Change)
Temp= ~600 C
Probe in pot-full of water
on hot plate
Probe in emptied pot
on hot plate
M. Kamat Jan, 2013

20. Heat Energy Must Be Provided for Sublimation to Continue:
What is the heat source
- From the heated shelves in the lyophilizer Chamber
(some cases: ambient heat, IR, MW etc.)
How to increase the rate of sublimation
- Increase the driving force
Increase the heat supply (shelf temperature)
Increase the product temperature
Limit: (maximum allowable temperature)
For every 10 ºC rise in product temp, the rate of drying doubles
M. Kamat Jan, 2013

21. Important The low pressure above the ice keeps the product frozen
The heat is transferred into the Vial
(Heat-Transfer)
The water vapor is transferred out of vial
(Mass-Transfer)
The two transfer processes must be equal to keep the product
frozen and sublimation process to continue
M. Kamat Jan, 2013

22. The Water Vapor Is Transferred Out of Vial
The vapor then flows out of chamber into the condenser section and gets deposited as ice on cold surfaces of condenser plates.
In old times :
chemical traps (P2O5, silica desiccants)
(and in food industry) directly to the pump/ballast (and then oil change)
The coldness of condenser does not affect the drying rate as long as it is colder than the product temperature
Above certain temperature, though, the ice condensation power may decrease
Very low condenser temperatures are not needed for sublimation to happen: Just collect the sublimate
M. Kamat Jan, 2013

23. Heat Transfer Phenomena
Flow of Heat :
Heating Medium Shelf Interior Shelf Surface
(thru the trays) Under the Vial Bottom Surface of Vial Bottom of Ice Through the Ice Sublimation Front
Rate of heat input =
Where,
 is the thermal conductivity of the container,
d is the thickness of the base of the container
Ts = Shelf temperature
Tc,i = Temperature at the ice interface
M. Kamat Jan, 2013

24. Mass Transfer Phenomenon
Vent
We will discuss
This later
M. Kamat Jan, 2013

25. M. Kamat Jan, 2013

26. Heat and Mass transfer processes
Energy (in) = Energy (out)
(heat) (sublimation)
Heat transfer rate = Hs X mass transfer rate
Rate of heat input = Heat of sublimation X Rate of mass transfer
M. Kamat Jan, 2013

27. Effect of Resistance to Mass Transfer
M. Kamat Jan, 2013

28. Key Process Parameters
Tp (product temperature): Keep the product below Tcritical
Pc (chamber pressure): Keep sublimation process on
Ts (shelf surface temp): Provide energy for sublimation
M. Kamat Jan, 2013

29. Factors Which May Affect the Cycle
Action Effect on Cycle
Increase Product temperature Short
Decrease dried product resistance Short
(Freezing modifications)
Use of Trays Long
Better Contact of Glass Short
Increase Chamber Pressure Short
(Up to certain limits)
M. Kamat Jan, 2013

30. Process Parameters Independent Parameters (all programmable variables)
Not affected by the characteristics
and the load of the product
Shelf Temperature (fluid)
Time Duration (soaks)
Ramping
Dependent Parameters
(non-programmable variables)
Affected by the characteristics and
the load of the product
Condenser Temperature
Chamber Pressure
Product Temperature
Product drying Time
M. Kamat Jan, 2013

31. Stages of Lyophilization
Fill the solution in the vials. Place stoppers
Freezing the product on FD Shelves
Start Cooling the condenser
Produce Vacuum in the dryer
Open the isolation Valve
Check Pressure and Heat the product
Start Primary drying
Continue with Secondary Drying
End-of-Drying
Stopper and Remove the Product
QC Testing
M. Kamat Jan, 2013

32. Schematics of a Lyophilizer
From: Sundaram et al; BioPharm International, Volume 23, Issue 9, Sep 2010
M. Kamat Jan, 2013

33. Lyophilizer Chamber
M. Kamat Jan, 2013

34. Lyophilizer Units
Condenser
Chamber
Vacuum Pumps
M. Kamat Jan, 2013

35. M. Kamat Jan, 2013

36. FREEZE DRYING OF COFFEE INVOLVES FOUR STEPS:
Pre-freezing coffee concentrate (40-45%) up to -5/-10 °C followed by foaming.
Freezing of the pre-frozen coffee liquor at -50 °C in a blast freezer.
Sizing of the fr0zen coffee particles to a granular size of 3X3mm.
Sublimation of the ice in a vacuum freeze dryer (VFD) under vacuum (0.5 torr) and controlled temperature.
M. Kamat Jan, 2013